Trk's are high affinity tyrosine kinase receptors that are activated by Neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are a group of soluble growth factors Nerve Growth Factor (NGF) which activates TrkA, Brain-Derived Neurotrophic Factor (BDNF) and NT-4/5 which activates TrkB, and Neurotrophin-3 (NT3) which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).
Inhibitors of the Trk/neutrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain. Antagonistic NGF and TrkA antibodies have been shown to be efficacious in inflammatory and neuropathic pain animal models and in human clinical trials. (Woolf, C. J. et al. Neuroscience 1994, 62, 327-331; Zahn, P. K. et al. J. Pain 2004, 5, 157-163; McMahon, S. B. et al. Nat. Med. 1995, 1, 774-780; Ma, Q. P. and Woolf, C. J. Neuroreport 1997, 8, 807-810; Shelton, D. L. et al. Pain 2005, 116, 8-16; Delafoy, L. et al. Pain 2003, 105, 489-497; Lamb, K. et al. Neurogastroenterol. Motil. 2003, 15, 355-361; Jaggar, S. I. et al. Br. J. Anaesth. 1999, 83, 442-448.)
It has been shown that NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in both mice and rats, it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine. Activation of the BDNF/TrkB pathway has been implicated in numerous studies as a modulator of marious types of pain including inflammatory pain (Matayoshi, S., J. Physiol. 2005, 569:685-695), neuropathic pain (Thompson, S. W. Proc. Natl. Acad. Sci. USA 1999, 96:7714-7718) and surgical pain (Li, C.-Q. et al. Molecular Pain, 2008, 4(28), 1-11). Because TrkA and TrkB kinases may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.
The association between overexpression, activation, amplification and/or mutation of Trk kinases and several cancers as seen with studies conduct on neuroblastoma (Brodeur, G. M. Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Kruettgen et al. Brain Pathology 2006, 16:304-310), prostate cancer (Dionne et al. Clin. Cancer Res. 1998, 4(8), 1887-1898), pancreatic cancer (Dang et al. j of Gastroenterology and Hepatology 2006, 21(5), 850-858), large cell neuroendocrine tumors (Marchetti et al. Human Mutation 2008, 29(5), 609-616), and colorectal cancer (Bardelli, A. Science 2003, 300, 949) support the reasoning that therapeutic implications of an effective Trk inhibitor may extend far beyond pain therapy. In preclinical models of cancer, non-selective small molecule inhibitors of TrkA, B and C were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. Cancer Letters 2001, 169:107-114; Meyer, J. et al. Leukemia 2007, 1-10; Pierottia, M. A. and Greco A. Cancer Letters, 2006, 232:90-98; Eric Adriaenssens, E. et al. Cancer Res 2008, 68(2), 346-351).
Also, inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of inflammatory lung diseases including asthma (Freund-Michel, V. et. al. Pharmacology & Therapeutics 2008, 117(1), 52-76), interstitial cystitis (Hu Vivian Y, et. al. The Journal of Urology 2005, 173(3), 1016-1021), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, F. F, et. al. Gut 2000, 46(5), 670-678) and inflammatory skin diseases such as atopic dermatitis (Dou, Y. C. et. al. Archives of Dermatological Research 2006, 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P. et. al. J. Investigative Dermatology 2004, 122(3), 812-819).
Modulation of the neutrophin/Trk pathway has also been shown to have an effect in the etiology neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease (Sohrabji, F. et. al. Neuroendocrinology 2006, 27(4), 404-414).
Recent literature has identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor-TrkA protein (Vaishnavi, A. et. al. Nature Medisine 2013, 19(11), 1469-1472).
The foregoing information is provided as background for understanding features of the invention and does not constitute an admission of prior art.